DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Perrault syndrome 2 — screening already-approved drugs against its 7-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePerrault syndrome 2 maps to a 7-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for perrault syndrome 2 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) — CLPP is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet diodrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1TG6 · 2.1 Å · ligand 1,4-DIETHYLENE DIOXIDE (DIO). Experimental structure, not a prediction.
What the evidence adds up to
In 2014, two families with Perrault syndrome — one Japanese, one European — were found to carry compound heterozygous mutations in C10orf2, which encodes the Twinkle primase-helicase essential for mitochondrial DNA replication. The Japanese sisters had p.Arg391His and p.Asn585Ser; the European sisters had p.Trp441Gly and p.Val507Ile. The same gene was already known to cause dominant progressive external ophthalmoplegia type 3 and recessive mitochondrial DNA depletion syndrome 7 (infantile-onset spinocerebellar ataxia). The authors concluded that Twinkle mutations cause Perrault syndrome with neurologic features and that the phenotypic and genetic heterogeneity of these disorders requires genomic definition.
A 2022 review listed five genes — TWNK, CLPP, HARS2, LARS2, HSD17B4 — as causes of Perrault syndrome, a rare genetic disease whose key feature is hearing loss in both sexes, usually bilateral and beginning at birth or in infancy. No numbers or patient counts were given in that review.
A 2025 study of two Han Chinese families with Perrault syndrome type 3 identified novel CLPP variants: compound heterozygous c.270+1G>C and c.355A>C (p.Ile119Leu) in one family, and a missense c.400G>C (p.Asp134His) plus a large deletion in the other. In vitro minigene assays showed the c.270+1G>C variant causes intron 2 retention and an alternative 5' splice site. Among 33 previously reported Perrault syndrome type 3 patients, 97% (31/32) had hearing loss, 55% (16/29) had neurological disease, and 71% (15/21) of females had primary ovarian insufficiency. Including the four new variants, 21 pathogenic CLPP variants have been reported (57% missense, 43% truncating). Biallelic truncating or missense-plus-truncating genotypes were associated with higher rates of neurological disease (p = 0.001) but not with a difference in hearing loss incidence compared to biallelic missense genotypes. The authors noted that diagnosis is challenging because of genetic and clinical heterogeneity.
A separate 2014 report described two sporadic and two familial new cases of sensorineural hearing impairment and ovarian dysgenesis, the cardinal signs of Perrault syndrome in females; only one had a nervous system defect. That study excluded GJB2, POLG, and FOXL2 as candidate genes but did not identify the causative mutations. No effective therapy or clinical trial for any Perrault syndrome subtype has been reported in these abstracts. What is missing is a systematic natural history study with sufficient numbers of patients, standardised neurological and audiometric phenotyping, and any interventional trial — drug or otherwise — that could test a treatment hypothesis. The genetic heterogeneity and small patient populations make trial design and patient stratification the main obstacles.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2014 · 108 citations · open access
Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features
AbstractOBJECTIVE: To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome. METHODS: Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry. RESULTS: In family 1, affected individuals were compound heterozygous for chromosome 10 open reading frame 2 (C10orf2) p.Arg391His and p.Asn585Ser. In family 2, affected individuals were compound heterozygous for C10orf2 p.Trp441Gly and p.Val507Ile. C10orf2 encodes Twinkle, a primase-helicase essential for replication of mitochondrial DNA. Conservation and structural modeling support the causality of the mutations. Twinkle is known also to harbor multiple mutations, nearly all missenses, leading to dominant progressive external ophthalmoplegia type 3 and to recessive mitochondrial DNA depletion syndrome 7, also known as infantile-onset spinocerebellar ataxia. CONCLUSIONS: Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.
Journal of Neuroscience and Neurological Research · 2022 · 2 citations · open access
The Role of Mutations on Genes TWNK, CLPP, HARS2, LARS2, HSD17B4 in Perrault Syndrome
AbstractPerrault syndrome was first reported by Dr. M. Perrault, a physician from Paris, in 1951. Perrault syndrome is a rare genetic disease that causes various signs and symptoms in men and women affected by this syndrome. One of the key features of this syndrome is hearing loss, which occurs in both men and women. In perrault syndrome, hearing problems occur due to changes in the inner ear, known as hearing loss. This disorder usually affects both ears of the patient and the first symptoms can start at birth or in infancy. Perrault syndrome has several genetic causes. However, researchers believe that perrault syndrome is caused by mutations in the TWNK, CLPP, HARS2, LARS2, and HSD17B4 genes.
CLPP Gene Variants Causing Perrault Syndrome Type 3 in Han Chinese Families: A Genotype-Phenotype Study
AbstractBACKGROUND: Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and primary ovarian insufficiency (POI) secondary to ovarian dysgenesis. However, the mutation spectrum of disease-causing genes for Perrault syndrome in the Chinese population remains poorly understood. In this study, we report on two Chinese families with Perrault syndrome type 3 caused by novel CLPP gene variants. We also conducted a comprehensive literature review of CLPP gene variants in Perrault syndrome type 3 to elucidate genotype-phenotype associations. METHODS: Using Whole Genome Sequencing (WGS) data, two pedigrees with Perrault syndrome type 3 were ascertained in the Chinese Deafness Genetics Cohort through genotype-driven analysis. Variants were validated using Sanger sequencing and copy number quantification methods. In vitro analysis of splice site variants in the CLPP gene using the minigene assay. RESULTS: Two Han Chinese families were ascertained: one with compound heterozygous variants (c.270 + 1G > C and c.355A > C [p. Ile119Leu]) and the other with missense variant (c.400G > C [p. Asp134His]) together with a large deletion in CLPP. In vitro minigene assays confirmed that the c.270 + 1G > C variant causes intron 2 retention and an alternative 5' splice site in exon 2, leading to protein alteration. Among 33 Perrault syndrome type 3 patients in literature, 97% (31/32) had hearing loss, 55% (16/29) neurological disease, and 71% (15/21) females had POI. Including our 4 novel variants, 21 pathogenic CLPP gene variants have been reported, with 57% (12/21) missense and 43% (9/21) truncating variants, mainly in the ATP-dependent Clp protease proteolytic subunit. Biallelic truncating or missense plus truncating genotypes showed higher rates of neurological disease (p = 0.001), but no significant difference in hearing loss incidence compared to biallelic missense genotypes was observed. CONCLUSION: This study highlights the challenges in diagnosing Perrault syndrome due to its genetically and clinically heterogeneity. By exploring novel variants and establishing genotype-phenotype correlations, we aim to improve the genetic diagnosis and consultation for this complex disorder.
American Journal of Medical Genetics Part A · 2014 · 0 citations
Proyecto básico y de ejecución de rehabilitación de vivienda unifamiliar, Vilar de Locrendes, municipio de Oza-Cesuras, provincia de La Coruña
AbstractWe report on two sporadic and two familial new cases with sensorineural hearing impairment and ovarian dysgenesis which are the cardinal signs of Perrault syndrome in females. Only one of them has a nervous system defect. We reviewed all the published cases of Perrault syndrome in order to define the clinical variability and to evaluate the frequency of the neurological anomalies in this clinical entity. Moreover we excluded GJB2, POLG, and FOXL2 as candidate genes in Perrault syndrome.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
